Download 2nd Lecture

PHL 472
Chemical Carcinogens
Abdelkader Ashour, Ph.D.
2nd Lecture
Genotoxic vs. Epigenetic Events
 Genotoxic carcinogen: one that reacts directly with DNA or with
macromolecules that then react with DNA.
 Epigenetics: modifications in gene expression that are controlled by heritable
but potentially reversible changes in DNA methylation and/or chromatin
structure.
 Epigenetic carcinogen: one that does not itself damage DNA but causes
alterations that predispose to cancer.
 DNA methylation is a type of chemical modification of DNA that can be
inherited and subsequently removed without changing the original DNA
sequence. As such, it is part of the epigenetic code and is also the most well
characterized epigenetic mechanism
Multistage Carcinogenesis

Multistage chemical carcinogenesis can be conceptually
divided into four stages:
1.
Tumor initiation
2.
Tumor promotion
3.
Malignant conversion
4.
Tumor progression
Multistage Carcinogenesis, Tumor Initiation
The primary genetic
change that results from a
chemical-DNA interaction
is termed tumor initiation.
Initiated cells are
irreversibly altered and
are at a greater risk of
malignant conversion than
are normal cells
A chemical carcinogen
causes a genetic error by
modifying the molecular
structure of DNA
Thus can lead to a
mutation during DNA
synthesis, mainly by
forming an adduct between
the chemical carcinogen or
one of its functional groups
and a nucleotide in DNA
 DNA adduct formation that causes either the activation of a proto-oncogene or the
inactivation of a tumor suppressor gene can be categorized as a tumor-initiating event.
 This leads to genomic instability and an acceleration in the genetic changes taking place
Multistage Carcinogenesis, Tumor Promotion
Tumor promotion comprises
the selective clonal
expansion of initiated cells.
(epigenetic effect)
Selective, clonal growth
advantage causes a focus of
preneoplastic cells to form.
Tumor promoters (e.g.,
croton oil, saccharin) are
generally non-mutagenic and
are not carcinogenic alone.
They reduce the latency
period for tumor formation
after exposure of a tissue to
a tumor initiator (mutation
rate ά rate of cell division)
Multistage Carcinogenesis, Tumor Promotion to
Malignant Conversion
 The total dose of a tumor
promoter is less significant
than frequently repeated
administrations,
if the tumor promoter is
discontinued before
malignant conversion has
occurred, pre-malignant or
benign lesions may
regress
 Tumor promotion contributes
to the process of
carcinogenesis by the
expansion of a population of
initiated cells, with a growth
advantage, that will then be at
risk for malignant conversion
Chemicals or agents capable of both tumor initiation and promotion are known as
complete carcinogens, e.g., benzo[a]pyrene
Multistage Carcinogenesis, Tumor Promotion to
Malignant Conversion
Additional genetic changes
(mutations) continue to
accumulate
The accumulation of
mutations, and not
necessarily the order in
which they occur, constitutes
multistage carcinogenesis
This scenario is followed by
malignant conversion, tumor
progression, and metastasis
Carcinogenesis requires the
malignant conversion of
benign hyperplastic cells to a
malignant state, and invasion
and metastasis are
manifestations of further
genetic and epigenetic
changes
Multistage Carcinogenesis, Malignant Conversion
 Malignant conversion is the
transformation of a
preneoplastic cell into one
that expresses the
malignant phenotype
 This process requires
further genetic changes
 A prominent characteristic
of the malignant phenotype
is the propensity for
genomic instability and
uncontrolled growth.
During this process, further genetic and epigenetic changes can occur, again including
the activation of proto-oncogenes (e.g., ras) and the functional loss of tumor suppressor
genes (e.g., p53).
Multistage Carcinogenesis, Tumor Progression
Tumor progression
comprises the expression of
the malignant phenotype and
the tendency of malignant
cells to acquire more
aggressive characteristics
over time.
Also, metastasis may involve
the ability of tumor cells to
secrete proteases that allow
invasion beyond the
immediate primary tumor
location.